IPA Bulletin
Recent Advances - Volume 22, Number 1
By Professor John
O'Brien, Dr. Robert Barber, and Professor Robert Baldwin
Cholinesterase inhibitors in Alzheimer disease — which one works best?
Ritchie et al (Am J Geriatr Psychiatry 2004;12(4):358-69) approached this question by undertaking a meta-analysis of the relative
efficacy and safety of donepezil, galantamine, and rivastigmine. After conducting an extensive electronic and manual search (January 1992 to July 2002), they compared the
findings of 21 studies against predefined clinical outcomes. In summary, donepezil, galantamine, and rivastigmine demonstrated similar cognitive
efficacy, with donepezil and rivastigmine showing a dose response effect. Estimates of clinical global improvement also demonstrated superiority over placebo for each drug, but with no observed dose effects. Both galantamine and rivastigmine were associated
with a greater risk of trial dropout than placebo, especially at higher dosing levels.
Long term treatment of Alzheimer’s disease using cholinesterase inhibitors Grossberg and colleagues from St. Louis, United States (Am J Geriatr Psychiatry 2004;12(4):420-31) followed patients with Alzheimer’s disease on rivastigmine for two years. They compared the clinical
course of AD patients on active treatment with a prediction of their course derived by a baseline-dependent historical model of disease progression developed from data in untreated AD patients. Overall, there was less cognitive decline on rivastigmine, and the magnitude of this gain was thought to be relevant to global patient functioning. From a wider perspective, Winblad and Jelic reviewed (Alzheimer Dis Assoc Disord. 2004;18 Suppl 1:S2) the long term findings from all cholinesterase inhibitors in AD. Interestingly, one of their conclusions was that patients who received continuous treatment with a cholinesterase inhibitor from the outset generally had better long-term outcomes than those who received placebo in the double-blind phase of the trials. They suggest better outcomes are observed if patients are both diagnosed and treated early.
Is donepezil an effective treatment of neuropsychiatric symptoms in Alzheimer disease? With concerns about the safe use of atypical antipsychotics in dementia, the need to know whether alternative treatments are effective is even more pressing. Holmes et al from Southampton, UK undertook a study to examine the efficacy of donepezil in the treatment of neuropsychiatric symptoms in patients (n=134) with Alzheimer’s disease (AD) (Neurology. 2004 27;63(2):214-9). The study had two phases. Firstly, patients with mild to moderate AD with prominent neuropsychiatric symptoms at baseline were treated openly with donepezil 5 mg daily for 6 weeks followed by 10 mg daily for a further 6 weeks. After 12 weeks of this open-label phase, there were
significant improvements in neuropsychiatric symptoms and distress compared with baseline. For the second stage, patients were then randomized to either placebo or 10 mg donepezil daily for a further 12 weeks. Patients who had continued on donepezil also had improvements in neuropsychiatric symptoms compared with the placebo
group. The authors concluded donepezil was efficacious in the treatment of neuropsychiatric symptoms in patients with mild to moderate AD.
Cholinesterase inhibitors in MCI — do they work? Evidence about the possible efficacy of cholinesterase inhibitors (CHI) in mild cognitive impairment (MCI) has been eagerly awaited, and if positive could have a major impact on the way we treat and manage early signs of emerging of Alzheimer’s disease. Salloway and colleagues from the United States have recently reported their findings from a study designed to evaluate the efficacy and safety of donepezil in MCI (Neurology. 2004;63(4):651-7). They enrolled 270 patients with MCI in a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Patients were randomized to receive donepezil (n = 133;5 mg/day for 42 days, followed by forced dose escalation to 10 mg/day) or placebo
(n = 137). Primary efficacy measures were the New York University (NYU) Paragraph Delayed Recall test and the Alzheimer disease (AD) Cooperative Study Clinician’s Global Impression of Change for MCI
(ADCS CGIC-MCI). There were a number of secondary efficacy measures, including the modified AD Assessment Scale-cognitive subscale (ADAS-cog) and various neuropsychologic measures. Overall, the primary efficacy measures did not show significant treatment effects in the intent-to-treat population. Some secondary measures showed effects favouring donepezil, but patients on donepezil
also experienced more adverse events than those on placebo. Given these findings, results from the three recently completed but not yet published 2 to 4 year long trial of galantamine (x2) and donepezil (x1) in MCI are awaited with interest, and hopefully will provide the necessary answers
about the longer-term efficacy and safety of CHI in MCI – watch this space!
Economic evaluation of a cholinesterase inhibitor in Alzheimer disease The cost-effectiveness of cholinesterase inhibitors (CHI) in Alzheimer’s disease (AD) is a controversial area — not least because of methodological constraints. As outlined by Wimo (Drugs Aging. 2004; 21(5):279-95), pharmacoeconomic evaluations of CHI have largely been retrospect
in nature and there has been only one published randomized clinical trial with empirical data with a cost consequence analysis design, indicating cost neutrality. The focus of a recent study by Feldman et al from Canada (Neurology 2004;63(4):644-50) was to investigate the costs to society of AD care in a multinational, randomized, placebo-controlled trial of donepezil in patients with moderate to severe AD. They found the mean total societal cost per patient for the 24-week period for donepezil was US
$6,686 and US $6,910 for placebo. This net cost saving of US $224 included cost of donepezil treatment. Most of the cost-saving was due to less use of residential care by patients, and caregivers spending less time assisting patients with ADL. The authors conclude that the cost-consequence analysis reveals economic
benefits of treatment of moderate to severe AD with donepezil.
Are there neurochemical changes which can distinguish major forms of degenerative dementias in life? Developments in single-photon emission computed tomography (SPECT) now allow differences in the integrity nigrostriatal dopaminergic function to be more robustly assessed during life. The question,
addressed by two recent studies, is whether this technology can detect measurable differences in dopamine neurotransmission between the major types of neurogenerative disease in late life? (Ceravolo et al J Neural Transm. 2004;111(8):1065-73; O’Brien et al, Arch Neurol. 2004;61(6):919-25). Both
studies used the (123)I-FP-CIT ligand, which provides a way to visualize the extent and pattern of dopamine transporter loss. Overall, patients with dementia with Lewy bodies (DLB) showed a significantly greater loss of striatal binding than those with Alzheimer’s disease (AD). Results from
O’Brien et al showed a good separation between DLB and AD (region of interest: sensitivity, 78%;
specificity, 94%; positive predictive value, 90%), but not among subjects with DLB, Parkinson Disease (PD), and PD with dementia. The results indicate that dopaminergic presynaptic function is relatively well preserved in AD, and that the dopamine transporter loss occurring in DLB can indeed be detected in life using FP-CIT SPECT.
The evolution of pathology in Alzheimer’s disease; which comes first? We now have a growing understanding of the neuroanatomical distribution of pathology in Alzheimer’s disease (AD), but how do these changes evolve over time? Ingelsson and colleagues from Boston, United States (Neurology. 2004;23;62(6): 925-31) set about trying to answer this question by determining the time when the key changes occur. They measured ADamyloid deposition, amyloid beta-peptide (Abeta) accumulation, neurofibrillary tangle (NFT) formation, synaptic loss, and gliosis-within the temporal association cortex of AD cases of varying disease duration, relative to control brains. They found
that in AD, the duration of dementia correlated with the degree of tangle formation, gliosis, and synaptic loss but not with any Abeta measures. Accumulation of Abeta, measured both neuropathologically and biochemically, was markedly increased in AD brains independent of disease duration. Interpreting their findings, they concluded it could indicate there is a distinct process
in the initiation and progression of AD pathology. Interestingly, the deposition of Abeta may reach a “ceiling” early in the disease process, whereas NFT formation, synaptic loss, and gliosis appears to continue throughout the course of the illness.
Neuropsychiatric symptoms in dementia — further genetic associations In the previous edition of the Bulletin we reported on the findings from Craig et al (Neurosci Lett. 2004;363(3):199-202.) supporting the notion that agitation in Alzheimer’s disease (AD) could be
genetically linked. Now further work from Assal et al has examined the association between the serotonin transporter and receptor gene polymorphisms and neuropsychiatric symptoms in AD (Arch
Neurol. 2004;61(8):1249-53). Based on available evidence, the authors hypothesized that 5-HT2A and 5-HT2C receptor
polymorphisms would be associated with agitation/aggression and psychosis in AD, whereas polymorphisms of the promoter region (5-HTTPR ) and intron 2 of the serotonin transporter gene (5-HTTVNTR) would be associated with agitation/aggression or depression and anxiety. The results from 96 subjects found evidence to support only the first part of their hypothesis — namely that 102T genotype of the 5-HT2A receptor was significantly associated with delusions and agitation/aggression.
They did not replicate previous associations between neuropsychiatric symptoms and 5-HT2C receptor polymorphism or 5-HTTPR polymorphism, nor did they ?and any link with 5-HTTVNTR polymorphism. In conclusion, they comment that 5-HT2A receptor polymorphism may contribute to the expression of psychosis and agitation/aggression in patients with Alzheimer disease, but the absence of other
positive associations may be due to the relatively small sample size and/or potentially small effect size of the polymorphisms and requires further study.
Are patients with mild cognitive impairment and depression at an increased risk of developing Alzheimer’s disease? Researchers from Spain (Modrego and Ferrandez, Arch Neurol. 2004; 61(8):1290-3) conducted a three-year prospective study (n=114 patients) to see whether patients with mild cognitive impairment (MCI) and depression had a higher risk of converting to Alzheimer’s disease (AD) than those without depression.
Overall, just over 50% of the sample developed AD during the study. Interestingly, of the 41 patients diagnosed as depressed at baseline, 35 (85%) developed dementia in comparison with 24 (32%) of the nondepressed patients (relative risk, 2.6; 95% confidence interval, 1.8-3.6). The survival analysis also showed that depressed patients developed dementia earlier than the nondepressed. Furthermore, they observed that most patients with
depression at baseline exhibited a poor response to antidepressants. In conclusion, the authors state that patients with MCI and depression are at
more than twice the risk of developing AD as those without depression. Patients with a poor response to antidepressants appear to be at an especially increased risk of developing dementia.
Sometimes results are not what you expect! — Part 1 An interesting neuroimaging study by Dickerson et al (Ann Neurol. 2004;56(1):27-35) found somewhat surprising results. They used functional MRI to assess the level of activation (to a visual encoding task) in the medial temporal lobe (MTL) of nondemented elderly subjects with mild cognitive impairment (MCI). Perhaps as would be predicted, greater activation within the MTL correlated with better memory performance at baseline. However, those subjects with MCI who subsequently declined over the 2.5 years
of clinical follow-up (44% of the sample) activated a significantly greater extent of the MTL during the encoding tasks, despite equivalent memory performance. The authors therefore hypothesized that increased activation in MTL regions reflects a compensatory response to accumulating AD pathology and may serve as a marker for impending clinical decline.
Sometimes results are not what you expect! — Part 2
No doubt, when circumstances conspire, we have all found ourselves encouraging a stressed caregiver to consider the option of 24-hour care for their relative with dementia. But what is the evidence this
move relieves their stress? An interesting study by Schulz et al ( JAMA. 2004;292(8):961-7) set about
answering this question by assessing the impact of placing a relative with dementia in a long-term care facility on caregivers’ health and well-being. This was a large prospective study involving a sample of 1,222 caregiver-patient dyads recruited from six US sites. A total of 180 patients were placed in a long-term care facility during an 18-month follow-up period. They obtained a detailed data set based on both pre and post placement measures. Overall, they found that caregivers who institutionalized their relative reported depressive symptoms and anxiety to be as high as they were while their relative was at home. These effects were most pronounced among caregivers who were married to the patient, visited more frequently, and were less
satisfied with the help they received from others. The use of antidepressants did not change
significantly before (21.1%) to after (17.9%)
placement, but the use of anxiolytics actually increased after placement 14.6% to 19%. Almost half
of the caregivers continued to visit the patient daily and provide help with physical care. Clearly, perhaps as expected, the transition to institutional care represents a particularly difficult time for
caregivers, and importantly there are ongoing signs of stress and distress even after placement. The authors make their case for a better range of clinical interventions to help prepare the caregiver for a placement transition and treat their depression and anxiety following placement.
A pilot study of a yoga and meditation intervention for dementia caregiver stress
Finding ways to help caregivers can be challenging. This small study from the United States (Waelde et al J Clin Psychol. 2004;60(6):677-87) enrolled 12 older female caregivers of patients with dementia
in a six-session manualized yoga-meditation program (called Inner Resources), designed to help caregivers cope with stress. Pre/post comparisons revealed statistically significant reductions in depression and anxiety and improvements in perceived self-efficacy. There was a dose-response in that greater improvements were observed with greater time spent practicing. Most caregivers seem to
find the intervention useful, and reported subjective improvements in physical and emotional functioning. Naturally, further studies are required before results can be generalized, but this approach offers, at least for some people, a novel intervention which may improve affect, coping, physical well-being, and stress management.
Psychosocial correlates of late-onset psychosis
Psychosis in late life is an important, well-recognized but poorly-understood illness. A study by Giblin et al (Int J Geriatr Psychiatry. 2004;19(7):611-23) although small, nevertheless revealed some important insights into this difficult-to-research condition. It focused on trying to clarify
the nature and extent of adverse early life experiences, presence of maladaptive cognitive schemas, and morale in relation to ageing. Subjects with a diagnosis of late-onset psychosis (LOP; n = 14) or
late onset depression (n = 13) and healthy older volunteers (n = 18) were compared. In summary, the main findings indicated subjects with LOP had high levels of adverse life experiences and distinct pattern of cognitive schema, particularly “other-directedness” and “over-vigilance/inhibition.” They also had low overall morale,
reflecting a high level of lonely-dissatisfaction. The authors viewed these findings to indicate life experiences, cognitive schemas and attitudes to ageing are important psychosocial correlates of LOP, and that these factors help to understand the emotional world of individuals who develop psychosis in later life. Whether they also, as the authors speculate, have
implications for developing more effective intervention approaches remains to be shown.
Neuropsychological deficits in depression Neuropsychological deficits in late-life depression are well described. In a study of 140 subjects aged over 60 (40 controls) Butters et al (Archives of General Psychiatry, 2004; 61: 587-595) showed that cognitive impairment was present across 5 domains of cognition (visuo-spatial, memory, executive, language and information processing).
Deficits appeared to be independent of overall medical burden and of APOE status. Of neuroimaging measures, neither cortical atrophy nor white matter lesions were associated with the
findings. Ventricular enlargement was linked to information processing speed, suggesting perhaps a subcortical disturbance. Also on the theme of cognitive
deficits in depression, Mojtabai and Olfson (Journal of the American Geriatric Society, 2004; 52: 1060-1069) examined a community sample of participants (n=661) meeting criteria for major depression. Using a cognitive test battery they found that those with deficits (eg word recall, Serial 7s, vocabulary, object naming and a summary score) were more likely to have persistent depressive symptoms. This study included both older
patients and those between the age of 50 and 64.
Stroke and depression Stroke is often closely linked with depression. Few studies have assessed the longitudinal impact of stroke. Whyte and colleagues (Journal of the American Geriatrics Society, 2004; 52:774-778) examined over a thousand subjects from a rural low social status population in America. (MoVIES study). They found that neither disability nor cerebrovascular risk factors explained the longitudinal association between stroke and depressive symptoms, the latter being six times more likely in stroke survivors over a two year period. The only cross-sectional illness associated with depression was diabetes
but this was not a long term predictor. This deepens the mystery surrounding the biological mechanisms linking brain damage and depression. Linked to the theme of brain changes in disorders linked to later life, such as depression and stroke, Schmidt et al ( Journal of the American Geriatric Society, 2004; 52: 1045-1050) evaluated 267 community dwelling people aged over 65. The aim was to assess the impact of silent stroke as seen on magnetic resonance imaging. The
definition of silent stroke was a lesion of 2 mm or less and a negative history of stroke from the participants. Silent stroke affected 13%
of this population - predisposition included the expected range of cardiovascular risk factors. Importantly though these lesions were associated with considerable impairment in: cognitive function, self-perceived health status and activities of daily living.
Treatment of depression in late life Is the debate about which antidepressant to give to older people over or not? Despite the rise and rise of the SSRIs Wilson and Mottram (International Journal of Geriatric Psychiatry, 2004; 19: 754-762) compared 537 recipients of tricyclics with 554 receiving SSRIs in a meta-analysis. All subjects were over 60. Those receiving “classical” tricyclics (Amitriptyline, Clomipramine, Doxepin and Dosulepin/Dothiepin) had a higher drop out rate, more serious side-effects and more adverse
effects, particularly dry mouth, drowsiness, dizziness and lethargy, than those receiving SSRIs. About 17% of the latter had troublesome problems, particularly nausea and vomiting. However when looking at
the tricyclic-related drugs (Mianserin and Trazodone) these fared about as well as the SSRIs and the authors concluded they are a worthwhile second line alternative to SSRIs.
Although not specifically of older people, a study by Zimmerman and colleagues (American Journal of Psychiatry, 2004; 161:1285-1289) is of interest to old age
psychiatrists. Treating physicians were asked about their antidepressant choices
immediately after prescribing, giving a “here and now” assessment of what factors might have
influenced prescribing. Citalopram was the most widely prescribed drug (23.3% of 1137 out-patients). Bupropion was the second (17.4%), Sertraline, Venlafaxine, Mirtazapine, Fluoxetine and Paroxetine followed. Tricyclics were only prescribed to 2.8%. The presence of insomnia, high levels of anxiety (which was very common) and fatigue were the most likely factors to
influence medication rather than DSM subtype, cost or even age. Many patients had major comorbidity which would have
excluded them from pharmaceutical funded research.
Antidepressants are not always effective because the patients do not take them.
“Concordance” is a new term to replace “compliance” with medication. Concordance therapy was piloted by Higgins et al (Journal of Affective Disorders, 2004; 81:287-291). In a mainly in-patient group of older people with depressive episode a manualized version of compliance therapy was found to be acceptable to patients with a trend towards slightly better outcomes at 3 months. Worryingly though 7 of the 26 subjects approached refused to take part and these are presumably the people most in need of this kind of help.
B12 and depression Vitamin B12 deficiency may increase the risk of depression. Hvas et al ( Journal of Affective Disorders, 2004; 81: 269-273) studied 140 older adults (mean age 75) in a randomized placebo controlled trial to assess whether Vitamin B12 has positive effects on cognitive impairment and depression. The baseline scores indicated that low B12 levels were associated with rather more
depressive symptoms but the intervention made no difference to cognitive impairment or mood. The authors comment that if B12 deficiency is associated with depression and cognitive impairment, the therapeutic window may be quite narrow.
John T. O’Brien, Robert Barber, and Robert Baldwin are the
Research Editors of the IPA Bulletin. They welcome readers’ comments via email
(J.T.O'Brien@ncl.ac.uk).
